Marsona,b, Mariana Freitas Fedato Valentec, Maira Migliari Brancoc, Camila Carbone Pradoc, Roberto José Negrão Nogueiraa,d

(1)

JPediatr(RioJ).2019;95(1):7---17

www.jped.com.br

REVIEW

ARTICLE

Influence

of

AIDS

antiretroviral

therapy

on

the

growth

pattern

夽

,

夽夽

Ana

Paula

Brigatto

Simões

Golucci

a

_,

_Fernando

_Augusto

_Lima

_Marson

a,b

_,

Mariana

Freitas

Fedato

Valente

c

_,

_Maira

_Migliari

_Branco

c

_,

_Camila

_Carbone

_Prado

c

_,

Roberto

José

Negrão

Nogueira

a,d,∗

a_Universidade_Estadual_de_Campinas_(UNICAMP),_Faculdade_de_Ciências_Médicas,_Departamento_de_Pediatria,_Campinas,_SP,_Brazil b_Universidade_Estadual_de_Campinas_(UNICAMP),_Faculdade_de_Ciências_Médicas,_Departamento_de_Genética_Médica,_Campinas,

SP,Brazil

c_Universidade_Estadual_de_Campinas_(UNICAMP),_Faculdade_de_Ciências_Médicas,_Hospital_de_Clínicas,_Campinas,_SP,_Brazil d_Faculdade_São_Leopoldo_Mandic,_Campinas,_SP,_Brazil

Received18October2017;accepted7December2017 Availableonline13April2018

KEYWORDS

Growth; Children; HIV;

Antiretroviraltherapy

Abstract

Objectives: Human immunodeficiency virusinfection can resultin the earlyimpairment of anthropometricindicatorsinchildrenandadolescents.However,combinedantiretroviral ther-apyhasimproved,inadditiontotheimmuneresponseandviralinfection,theweightandheight development ininfected individuals.Therefore,theobjectivewas toevaluatetheeffectof combinedantiretroviralonthegrowthdevelopmentofhumanimmunodeficiencyvirusinfected childrenandadolescents.

Sourceofdata: Asystematicreviewwasperformed.Inthestudy,thePRISMA(Preferred Report-ing Items for Systematic Reviews and Meta-Analyses) strategy was used as the eligibility criterion.TheMEDLINE-PubMedandLILACSdatabasesweresearchedusingthesedescriptors: HIV,children,growth,antiretroviraltherapy.Theobjectivewasdefinedbythepopulation, inter-vention,comparison/control,andoutcome(PICO)technique.Inclusionandexclusioncriteria wereappliedforstudyselection.

Synthesisofdata: Ofthe549studiesindexedinMEDLINE-PubMedandLILACS,73werereadin full,and44wereincludedinthereview(33showedapositiveimpactofcombinedantiretroviral therapyonweight/heightdevelopment,tenonweightgain,andoneonheightgaininchildren andadolescentsinfectedwithhumanimmunodeficiencyvirus).However,theincreaseingrowth wasnotenoughtonormalizetheheightofinfectedchildrenwhencomparedtochildrenofthe sameageandgenderwithouthumanimmunodeficiencyvirusinfection.

夽

Pleasecitethisarticleas:GolucciAP,MarsonFA,ValenteMF,BrancoMM,PradoCC,NogueiraRJ.InfluenceofAIDSantiretroviraltherapy

onthegrowthpattern.JPediatr(RioJ).2019;95:7---17.

夽夽

StudyconductedattheFaculdadedeCiênciasMédicas,UniversidadeEstadualdeCampinas,Campinas,SP,Brazil.

∗_{Corresponding}_author.

E-mail:nutrigene@uol.com.br(R.J.Nogueira).

https://doi.org/10.1016/j.jped.2018.02.006

(2)

8 GolucciAPetal.

Conclusions: Combinedantiretroviraltherapy,whichisknowntoplayaroleintheimprovement ofviralandimmunologicalmarkers, mayinfluenceintheweightandheightdevelopmentin childreninfectedwithhumanimmunodeficiencyvirus.Theearliertheinfectiondiagnosisand, concomitantly,ofmalnutritionandthestartofcombinedantiretroviraltherapy,thelowerthe growthimpairmentwhencomparedtohealthychildren.

PALAVRAS-CHAVE

Crescimento; Crianc¸as; HIV; Terapia antirretroviral

InfluênciadaterapiaantirretroviralparaaAIDSnopadrãodecrescimento

Resumo

Objetivos: A infecção pelovírus da imunodeficiênciahumana podecomprometer, precoce-mente, os indicadores antropométricos de crianças e adolescentes. No entanto, a terapia antirretroviralcombinadatemmelhorado,alémdarespostaimunológicaedainfecçãoviral, oganhopôndero-estaturaldosinfectados.Dessaforma,nossoobjetivofoiavaliaroefeitoda terapiaantirretroviralcombinadanocrescimento,decriançaseadolescentes,infectadaspelo vírusdaimunodeficiênciahumana.

Fontedosdados: Foirealizadaumarevisãosistemática.Noestudo,adotou-secomocritériode elegibilidadedosartigos,aestratégiaPRISMA(preferredreportingitemsforsystematicreviews andmeta-analyses). Foram consultadas asbases de dadosMEDLINE-PubMed e LILACSpelos descritores:HIV(vírusdaimunodeficiênciahumana),children,growth,antiretroviraltherapy. Oobjetivofoi definidopela estratégia PICO(population,intervention, comparison/control,

outcome).Critériosdeinclusãoeexclusãoforamaplicadosnaselec¸ãodosestudos.

Síntesedosdados: Dos549estudosindexadosnoMEDLINE-PubMedeLILACS,73foramlidosna íntegra---44incluídosnarevisão(33demonstraramimpactopositivodaterapiaantirretroviral combinadanoganhopôndero-estatural,deznoganhodepesoeumnodeestatura,emcrianças eadolescentes,infectadoscomvírusdaimunodeficiênciahumana).Noentanto,oincremento nocrescimentonãofoiosuficienteparanormalizaraestaturadecriançasinfectadas,quando comparadocomcriançasdamesmaidadeesexo,seminfecçãopelovírusdaimunodeficiência humana.

Conclusões: A terapiaantirretroviral combinadaque, conhecidamente,atua namelhorade marcadores virais eimunológicos, podeinfluenciar noganho pôndero-estatural decrianças infectadas com vírus da imunodeficiência humana. Quanto mais precoce o diagnóstico da infecçãoe,concomitante,desnutriçãoeiníciodaterapiaantirretroviralcombinada,menores serãoosprejuízosnocrescimento,quandocomparadoàscriançassaudáveis.

eumartigoOpenAccesssobumalicenc¸aCCBY-NC-ND(http://creativecommons.org/licenses/ by-nc-nd/4.0/).

Introduction

Overallaspects

Acquired immunodeficiency syndrome (AIDS) is an infec-tiousdiseasecausedbythehumanimmunodeficiencyvirus (HIV), which qualitatively and quantitatively affects the CD4+ _T _lymphocytes _(CD4+ _TL).1 _Vertical _HIV

transmis-sioninchildhoodcanoccur atthreedistinctmoments: (i) intrauterine-transplacental transmission; (ii) during labor and/ordelivery;and(iii)throughbreastfeeding.Mostcases (about 65%) occur during labor and delivery, with the remaining35%occurringthroughintrauterinetransmission, especiallyinthelastweeksofgestationandwhen breast-feeding.Breastfeeding,asatransmissionrisk,isresponsible for7%to22%ofinfectioncases.1

Global data for 2016 estimate that 36.7 (30.8---42.9) million individuals, of whom2.1 million are children, are

infected with HIV.2 _In _Brazil,_from ₁₉₈₀ _to _2016, _842,710

cases of HIV infection were identified, of which approxi-mately 24,900 represent children under 14 years old --- a numberthatispossiblyunderestimated.3,4

Individuals infected with HIV have a reduction in the number of CD4+ _TL _--- _a _hallmark _{characteristic} _of _the

immunologicalsystem status. The mechanism that results infailuretoreconstituteCD4+_TL_has_not_been_fully

eluci-dated,butitincreasestheriskofopportunisticinfections.In additiontoimmunologicalchanges,therearenutritionaland endocrine-metabolic problems in AIDS, with HIV infection beingassociatedwithgrowthimpairment.5

GrowthdeficiencyinAIDS

(3)

AIDSandgrowthpattern 9

normalrangeforage---togrowthinterruptionandwasting syndrome.6_Growth_retardation_is_a_disease_severity

progres-sionindicatorandariskfactorfordeathinindividualswith AIDS.7_Moreover,_growth_deficiency_is_{multifactorial}_in_AIDS,

resultingfromtheeffectofantiretroviraltherapy,aswell asotherfactorsdescribedbelow:

(i) malnutrition:mayoccurmainlyduetoinadequate nutri-tional intake secondary to anorexia, oral or upper digestivetractlesions(infectiouscause),intake reduc-tion (psychological or economic cause), or nutrient malabsorption (chronic diarrhea).8 _Another _important

aspect is the acceleration of protein catabolism and increased metabolic expenditure secondary to uncon-trolledviralreplicationandtheresultinginflammatory response(includingcytokinenetworkdysregulation),as wellasopportunisticinfectionsorneoplasmssecondary to immunosuppression.2 _{HIV-associated} _malnutrition

wastermedwastingsyndrome9_;

(ii) gastrointestinal disorders (malabsorption): may result fromtheHIVinfection,opportunisticinfections(enteric parasites, such as Cryptosporidium, Mycobacterium avium-intracellulare,andcytomegalovirus,among oth-ers) or neoplasms. Diarrhea, abdominal pain, and dysphagia are commonly observed in HIV-infected patients;however, intestinalmalabsorptionmayoccur in children with or without diarrhea.10 _Damage _to

mucosal integrity and increased permeability favor intestinal dysfunction, leading to the malabsorption of fats,carbohydrates, and proteins, interfering with weightandheightdevelopment.Intestinaldysfunction mayadverselyinterferewiththeabilitytoabsorboral medications,includingzidovudine(AZT,C10H13N5O4)11;

(iii) stress: in AIDS, the expression of cytokines,including interleukins(1and6),tumornecrosisfactor-alpha,and interferonisaltered,promotingmetabolicstress,which mayleadtolossofappetite,anorexia,andcatabolism9_;

(iv) chronic disease: HIV infection leads to a progressive reductionoftheimmunefunction,withareductionin thenumberofCD4+_TL,_concomitant_to_changes_in_the

function of these cells and the main immune regula-tory pathways.Therefore,the susceptibilitytorepeat infections and antibody deficiencies alter metabolism through infection and/or intake reduction and, thus, patientnutritionalmonitoringisrequired8_;

(v) endocrine disorders: hormonal changes are probably caused by the viral infection itself or are secondary to endocrine glandinvolvement, due to opportunistic infections and/ormedicationsusedtotreatinfections and/ortheircomplications.12

Hence, it is important to assess factors associated with growth deficit, reinforcing the need to broaden theirunderstandinginordertominimizenutritionalstatus losses.11_Adequate_monitoring_by_the_{multidisciplinary}_team

contributes tothe early detectionof opportunistic infec-tions, metabolic and hormonal changes, decreased food intake, nutrient malabsorption, and socioeconomic prob-lems, probablyresulting in benefits to weight and height development.12

Antiretroviraltherapy---generalaspects

The1990swereamilestoneinthetreatmentofAIDS,with theuseof moreeffectiveantiretroviralregimens ---highly activeantiretroviraltherapy.Initially,antiretroviraltherapy wasbasedonAZTmonotherapy,butitshowedlowefficacy, requiringaprogressivecombinationofdrugs.Subsequently, dualtherapywasintroduced,withtheuseofnewnucleoside analogreverse-transcriptase inhibitors.Subsequently, pro-tease inhibitors and non-nucleoside reverse-transcriptase inhibitors appeared --- a three-drug regimen that was referredtoascombinedantiretroviraltherapy(cART).cART reducedHIVmortality,mainlyindevelopedcountries.6,13

Since 1996, cART has been used in childhoodto mini-mizediseaseprogression. Itisestimated thatwithout the useofantiretroviraltherapy,one-thirdofHIV-infected chil-drenwoulddiebeforeonemonth,andmorethanhalfbefore twoyearsofage.14

Antiretroviraltherapy---associationwith anthropometricandotherdata

Antiretroviral therapy in childhood and adolescence can result in metabolic disorders, mitochondrial toxicity, and adverse effects on nutritional status, especially in the firstmonthsoftreatment. Patientsmaydevelopnauseaor vomiting,lipodystrophy,andreducedbonemineralization.2

Diagnosisandtreatmentofmalnutritionisnecessary,since micronutrientdeficiency,especiallyofvitaminsA,C,E,D, andminerals (e.g.,seleniumandiron),alterstheimmune system (which is already altered in AIDS) and reduces growth.2

In adults, the duration of cART increases the risk of cardiovasculardisease(stroke,infarction,anddilated car-diomyopathy). Thus, it is suggested that children using antiretroviralsarelikelytohaveahigherriskofmorbidity andprematurecardiovascularmortality.3_Moreover,_immune

activation, with persistent chronic inflammation in HIV-infectedindividuals,alsoincreasestheriskofcardiovascular diseaseandotherdiseasesofinflammatoryorigin.Increased levelsofinflammatory markers (C-reactive protein, inter-leukin6, D-dimer, fibrinogen) associated with the risk of atherosclerosisandcancer,for instance, arealsofound in AIDS, and remain elevated regardless of the response to cART.15_Finally,_treatment_adherence,_which_includes_the_use

ofcART, constitutesa challenge,mainly in childhoodand adolescence,due tothe chronic drug use, esthetic alter-ationsrelatedtolipodystrophy,andpsychosocialaspects.16

Growthinchildhoodandadolescenceis crucial;hence, inthepresence ofAIDS, thepositive andnegativeimpact of cART should be assessed. Thus, the aim of this sys-tematic review was to evaluate the association between antiretroviraltherapyand growthin HIV-infectedchildren andadolescents.

Method

(4)

10 GolucciAPetal.

Titles identified after searching the ME DLINE-PubMed database (n = 98)

Titles identified after searching the LILACS

database (n = 63)

Evaluated titles (n = 161)

Titles after removal of duplicates and read of abstracts (n = 92)

Evaluated full-text articles in details (n = 73)

Articles included in the systematic review (n = 44) Articles excluded by titles

and abstracts (n = 69)

Excluded after full-text read (n = 19)

Iden

tifi

c

a

ti

on

Scr

e

en

ing

El

ig

ib

ili

ty

Inc

lus

io

n

Evaluated full-text articles (n = 92) Articles identified in the databases (n =

549)

Excluded after full-text reading in details (n = 29)

Figure1 Flowdiagramofarticleselectionusedinthesystematicreview.LILACS,LatinAmericanandCaribbeanLiteraturein

HealthSciences;MEDLINE-PubMed,MedicalLiteratureAnalysisandRetrievalSystemOnline---PublicMedline.

outcome(PICO)techniquewasusedtoestablishthestudy objective,asfollows:P,childrenandadolescentsfrom0to 19yearsofage;I,individualsusingcART;C,childgrowth; O,changeingrowthpattern.

In the PRISMA strategy, the inclusion of studies pub-lished from 1996 (year of cART start) to September 2017 wasselected.Originalarticlespublishedinjournalsindexed in the English languagewere included. It wasdecided to includealltypesofstudies,andamongtheselectedarticles, theclassificationwasmadeby degreeof recommendation andlevelofevidence.

The searches were carried out in the Medical Litera-tureAnalysisandRetrievalSystemOnline(MEDLINE-PubMed) and Latin American and Caribbean Health Sciences Liter-ature (LILACS)databases,using the following descriptors: antiretroviraltherapy,children,growth,HIV.Thefollowing filterswereused:(i)presenceofthedescriptorsinthetitle and/orabstract;(ii)publicationsinthe last21years;(iii) being a scientific article. The excluded articles were: (i) thosethathadaduplicatein anotherelectronicdatabase

ofthebibliographicsearch;(ii)thoseaboutthecostofAIDS treatment,withoutaddressinggrowth;(iii)thoseincluding childrenexposedtoHIV,butnotinfected;(iii)thoseon peri-natalgrowth;(iv)thoseaboutcARTuseinpregnantwomen; (v)thoseabouttheexclusiveuseofoneortwoantiretroviral drugs.

(5)

Tables 1 and 2.17---57 _Therapeutic _{interventions} _performed

withatleastthreeantiretroviraldrugswereincluded, with-outconsideringthecARTtype.

Results

ThedataobtainedaresummarizedinTables1and2.After the summation of the assessed studies, a population of 51,992HIV-infectedindividualswasincluded.Inthestudies, the positive responseto cART, withgrowth improvement, wasobservedin34articles.However,concurrent improve-ment in weight and height development occurred in 33 studies. Moststudies emphasizedthe importance ofearly diagnosisofHIVinfectioninchildrenandadolescents, aim-ingtodelayAIDS progressionandstart theuseofcARTas earlyaspossible.

In theliterature, cARTisassociated withimprovement in anthropometric and survival indexes. In the review, it wasobservedthat42,203/51,992(81.17%)childrenshowed improvementinthegrowthpatternwiththeuseofcART.

Ofthearticlesincludedinthereview,42haveadegree ofrecommendationB([i]onewithlevelofevidence2A;[ii] 35withlevelofevidence2B;[iii]sixwithlevelofevidence 2C)andtwoarticleshave levelof evidence1B(degreeof recommendation A). Article classification for the level of evidencewasperformedaccordingtorecommendationsof theOxfordCentreforEvidence-basedMedicine.

Fig.2brieflyshowsthegrowth-relatedoutcomes regard-ingtheuseofcARTinHIV-infectedchildrenandadolescents.

Discussion

Changesin growtharecommonin HIV-infectedchildren.58

Growth disorders may be associated with: (i) opportunis-tic infections associated with the disease; (ii) absence of immunological and viral control at the follow-up; (iii) metabolicchangesassociatedwithHIV.50_However,_after_the

startofcART,changesingrowthpatternhavebeenusedas effectivenessparametersinthetreatment ofchildrenand adolescentswithHIV.

Basedonthisreviewcarriedoutoverthelast21years, itcanbeobservedthatmostofthestudiesshoweda pos-itiveassociation inthe height-ageandweight-ageZ-score withtheuse ofcART(Table1). Inadditiontothe anthro-pometric improvements, the literature demonstrates that cARThasshownadecreaseinmorbidity,mortality,and hos-pitalizationlevelsofpatientsinfectedwithHIV.Treatment withcARTincreasesCD4+_TL_counts,_reduces_viral

replica-tion,andpartiallyrestorestheimmunesystem.Asaresult, itreducestheincidenceofopportunisticinfections.54,58 _In

2003,Benjaminetal.reportedthatchildrenusingcARThad feweralterationsintheimmunesystem,abetterresponse tothevirus,andabetterheight-ageZ-scorecurve.4_Verweel

etal.,in2002,showeddecreasesof63.69%in hospitaliza-tionsaftertheintroductionofcART.54

The literaturesuggeststhatchildren whowere treated in the past with monotherapy or dual therapy showed a temporaryimprovementinthegrowthrate.However,cART results in a lasting increase in the weight and height of infectedchildren.Thisincrease,however,didnotreachthe values closeto those of the general population. In 2008,

Buonoraetal.demonstratedthat,evenwithcART,infected patients had lower growth parameters than the non-HIV infected population.41 _Another _study _assessed _that, _after

theintroduction ofcART, weight-ageZ-score wascloseto thatofthepopulationwithoutHIVinfection,regardlessof thetimeoftreatmentstart.Inturn,theheight-ageZ-score remainedlow.26 _Similar_findings_were_observed _in_Europe,

whereaftercomparinggrowthcurvesofinfectedand non-infectedchildrenfor tenyears,itwasconcludedthatHIV infectionresultsinslowergrowthratesandthatthe differ-encesincreasewithage.53

Younger children may show greater weight and height recoveryafterthestart ofcART. Nachmanetal. reported in2005thatchildrenyoungerthantwoyearsofagehada higherheightZ-scoreduringtherapy.49_Weight_gain_was_also

predominantlyhigherinyoungerpatients.49 _In_2013,_Shiau

etal.evaluatedafour-yearfollow-upof195AIDSpatients andshowedthatpatientswhostartedcARTbefore6months of age showed a faster improvement in weight-age and height-ageZ-scoresthanthosewhostartedtherapylater.26

Therefore,theearlierthecARTisinitiated,thelowerthe growthdeficit.26,37

Anotherimportantfindingindicatedinthestudiesrefers tothenutritionalstatusbeforetreatment, asitcan influ-encethe anthropometricoutcomes afterthe introduction ofcART.BandyopadhyayandBhattacharyyashowedin2008 thatmalnourishedchildren haveworse resultsin the evo-lution of weight-age and height-age Z-scores compared tothose who started therapy under adequate nutritional conditions.44

Inthereview,oneofthemainlimitationswasthe inclu-sionofmanystudiesconductedinAfrica,wherenutritional deficiencymayindirectlyinfluencegrowthcontrolandmay representabiasintheuseofcART.Malnutritionandgrowth retardationoccurearlyinHIVverticaltransmission,andthe negativeimpact of chronic infection and nutritional defi-ciencyongrowthmaybeirreversible.32 _However,_the_lack

ofgrowthpatternimprovementoccurredinstudiescarried outduringashortperiodoftime.Forinstance,inthe2011 studybyDevietal.,whoassessed102patientsonlyinthe firstyearofcARTuse.32

Furthermore,thereviewdidnotcomparetheimpactof differentcombinedantiretroviraltherapieswitheachother. Furthermore,itwasnotpossibletoanalyzegrowthbyage group. None of the studies compared groups undergoing cART,withandwithoutvirologicfailure,toassessgrowth.

Some studies have alsohighlighted the need to assess drug interactions in children and the potential adverse effectsofcARTonmetabolism,butstudiesarestillscarcein thisagegroup.Itisnoteworthythatthepossiblemetabolic effects of cART include insulin resistance, dyslipidemia, hyperlactatemia, and that such changes may lead to an increasedriskforcardiovasculardiseasesanddiabetes.The elevationoftotalcholesterolandlipodystrophyassociated withtheuseofcARTremainsachallengeinthetreatmentof thesepatients.Factorsassociatedwithchildren’sadherence tocARTshowedthatlowadherencewasstronglyassociated withthe caregivers’profile(low levelof schoolingand/or degreeofpoverty).

(6)

12

Golucci

AP

et

al.

Table1 Dataobtainedfromthestudiesaccordingtoyearofpublication,studylocation,studydesign,assessedsample,mainresultsobtained,degreeofrecommendation,

andlevelofevidence.

Study(year) Location Studydesign Subjects Mainresults DR LE

Jessonetal.(2017)10 _Africa _Prospective_cohort

6months

158children 1to15yearsold

ImprovementinweightZ-scoreandanemiareduction B 2B

Ramtekeetal.(2017)9 _Africa _Longitudinal

cohort 1year

553children(300 controls) 4to9yearsold

ImprovementinweightandheightZ-scores.However,weightand heightwerenotwithinthenormalityparameterswhencompared withthecontrolgroup

B 2B

Camesetal.(2017)8 _Senegal _Prospective_Cohort

2years

ImprovementinheightZ-score B 2B

Ebissaetal.(2016)17 _Ethiopia _{Retrospective}

Cohort 2years

ImprovementinweightandheightZ-scoresandincreaseofCD4+

TLlymphocytes

Theeffectwasgreaterinunderweightchildren

B 2B

Achanetal.(2016)18 _Africa _Randomized_trial

3years

129children

2monthsto6yearsold

ImprovementinheightandweightZ-scores B 2B

Huetal.(2016)19 _China _{Retrospective}

Cohort 2years

ImprovementinweightandheightZ-scores B 2B

Feuchtetal.(2016)20 _South_Africa _{Observational}

cohort 3years

159children Lessthan5yearsold

ImprovementinweightandBMIZ-scoresinthefirst12months, andintheheightZ-scoreover3yearsoffollow-up

B 2B

Schomakeretal.(2016)21 _Africa _Prospective_cohort

3years

ImprovementinweightandheightZ-scoresandincreaseinCD4+

TLlevels

B 2B

Tekleabetal.(2016)22 _Ethiopia _Prospective

3months

ImprovementinweightandheightZ-scores B 2C

Chattopadhyayetal. (2016)23

India Cross-sectional 1year

56children (60controls) 2to10yearsold

Yotebiengetal.(2015)24 _Africa_and

Asia

Retrospective 2years

Improvementinweight-ageZ-scores B 2B

Kariminiaetal.(2014)25 _Asia _{Retrospective}

cohort 9years

2608patients 0to15yearsold

Shiauetal.(2013)26 _South_Africa _Prospective

4years

ChildrenwhostartedcARTbefore6monthsofageshoweda fasterimprovementinweightandheightZ-scoreswhencompared tothosethatstartedthetherapylater

B 2B

Chhaganetal.(2012)27 _Africa _Prospective

2years

151

prepubertalchildren

Gsponeretal.(2012)28 _Africa_and

SouthAfrica

Retrospective cohort

17,990patients 0to10yearsold

ImprovementofweightandheightZ-scores.However,theweight andheightfortheparameterswithinthenormalitycurveforage werenotreached

(7)

AIDS

and

growth

pattern

13

Table1 (Continued)

Sutcliffeetal.(2011)29 _Zambia _Prospective_cohort

2years

ImprovementinweightandheightZ-scores.Theeffectwas higherinunderweightchildren,andthelowerheightZ-score occurredinchildrenolderthan5years.After2yearsof treatment,alargeproportionofthechildrenremainedbelow weightandheightforage

B 2B

McGrathaetal.(2011)30 _Kenya _Prospective_cohort

4years

ImprovementinweightforageZ-score,whichwashigherin childrenunder6years.Therewasnoimprovementinheight Z-score

B 2B

Dinizetal.(2011)31 _Brazil _{Retrospective}

3years

BetterimmuneresponseandweightandheightZ-scoreswere observedattheendofthefollow-up

B 2B

Devietal.(2011)32 _India _Prospective

1year

102patients

Meanage=74months

InthefirstyearofcART,therewasimprovementintheimmune responseandweightZ-score,butnotheightZ-score

B 2B

Naidooetal.(2010)33 _South_Africa _{Retrospective}

8months

120children ImprovementinweightandheightZ-scores.Therewasnoeffect ontheheightofchildrenwithseveremalnutrition.Therewasan increaseinCD4+_TL_lymphocytes_and_a_reduction_in_viral_load

B 2C

Chantryetal.(2010)34 _USA _{Prospective/cohort}

---48weeks

97patients--- 1month to13yearsold (incomplete)

IndividualsstartingorswitchingtocARTwerecomparedtothe controlgroup(HIV-exposedbutuninfectedchildrenand

demographicandanthropometricdatafromanAmericanstudy). TherewasimprovementinweightandheightZ-scores,butno changeinBMIZ-score.However,weightandheightwerelower thanthoseofthehealthypopulation

B 2B

Yotebiengetal.(2010)35 _South_Africa _Prospective_cohort

---4years

ImprovementinweightZ-score,butnochangeinheightZ-score. Additionally,therewasanimprovementinCD4+_TL_count

A 1B

Weigeletal.(2010)36 _Malawi,_Africa _Prospective_---₂₄

months

307patientsyounger than15yearsold

Therewasanassociationbetweenimmunologicalresponseand weightandheightZ-scoreimprovementattheendofthe follow-up

B 2C

Musokeetal.(2010)37 _Uganda,_Africa _Prospective_---₄₈

months

130patients 6monthsto12years old

IncreasedweightandheightZ-scores,withtreatment,especially inindividualswhostartedthetherapyatayoungerage

B 2B

Aurpibuletal.(2009)38 _Thailand _Cohort_{--- 5}_years ₂₂₅_patients

0to15yearsold

ComparedwithanthropometricreferencedataforThaichildren, withnocontrolgroup.Therewasapositiveeffectonweightand heightZ-scores.Atthesametime,therewasanincreaseinCD4+

TLcount

B 2B

Daviesetal.(2009)39 _South_Africa _Prospective_cohort

--- 9years

Kabueetal.(2008)40 _Uganda _{Retrospective}_{--- 3}

years

749patients--- 0to19 yearsold

Improvementinweight-ageandheight-ageZ-scores.Theviralor immunologicalresponsewasnotassessed.Moreover,thestudy doesnotspecifytheuseofHAART

B 2B

Buonoraetal.(2008)41 _Brazil _{Retrospective}_{--- 97}

months

EvenwithHAART,height-ageandweight-ageZ-scoreswerelower thanthoseofhealthyindividuals

(8)

14

Golucci

AP

et

al.

Table1 (Continued)

Kekitiinwaetal.(2008)42 _United_Kingdom _Prospective_---₁₂

months

1458children Meanage5and7.6 yearsold

Improvementinweight-ageandheight-ageZ-scores,especiallyin youngerchildren

B 2A

Jaspanetal.(2008)43 _South_Africa _{Retrospective}

cohort---4years

391patients 9to59months

ImprovementinweightZ-score,butheightwasnotevaluated. Additionally,increasedCD4+_TL_levels_were_observed

B 2B

Bandyopadhyayand Bhattacharyya(2008)44

India Prospective---18 months

123

2monthsto8yearsold

MalnutritionbeforethestartofcARTmightimpairtheoutcomein nutritionalparameters;therewasanimprovementonlyinthe weightZ-score

B 2B

Zhangetal.(2007)45 _China _Prospective_---₁₂

months

83children---7to13 yearsold

ImprovementinweightandheightZ-scoresandthe immunologicalresponseofpatients

B 2B

Wamalwaetal.(2007)46 _Kenya,_Africa _Prospective_---₉

months

67children

18monthsto12years old

Improvementinweight-ageandheight-ageZ-scores.Additionally, theclinicalresponseandviralcontrolshowedbetterresultswith theuseofHAART

B 2B

Songetal.(2007)47 _Kenya,_Africa _{Retrospective}_---₁

year

29children---Mean age=8.5yearsold

Improvementinweight-ageZ-score B 2B

Guillenetal.(2007)48 _Spain _{Retrospective}_---₅

years

ImprovementinweightandheightZ-scoresandviralcontrolin thefirst5yearsofcART

B 2B

Nachmanetal.(2005)49 _USA _Prospective_---₂

years

192children 4monthsto17years old

HAARTallowedanincreaseinweight-ageZ-scoreatweek48and height-ageatweek96.Youngerchildrengainedweightinless time

B 2B

Lodhaetal.(2005)50 _India _Prospective_---₆

months

48children---mean age=5.6yearsold

Improvementinweight-ageZ-scoreduringthe6-monthperiod B 2C

Ghaffarietal.(2004)51 _USA _Prospective_---₂

years

BetterimmuneresponseandhigherweightandheightZ-scoresat theendoffollow-up

B 2B

Klineetal.(2004)52 _Romania _Prospective_---₆₇

weeks

ImprovementinweightandheightZ-scoresandimmunological response

B 2C

Newelletal.(2003)53 _Europa₍₁₁

countries)

Prospective---10 years

ImprovementinweightandheightZ-scoreswithcART,regardless ofclinicalclassification

B 2B

Verwelletal.(2002)54 _Netherlands _Prospective_study ₂₄_children_---₄_months

to16yearsold(96 weeksoftreatment)

Nocontrolgroupwasincluded,butratherreferencecurvesfrom theNetherlands.ImprovementinweightandheightZ-scoresin patientswithreducedviralloadandBMIZ-scoreinpatientswith advancedstageofdiseaseandmalnutrition

B 2C

Nachmanetal.(2002)55 _USA _Prospective_---₁₂₀

weeks

197patients---2to17 yearsold

Itwasfoundthatthegrowthdeficitincreasedovertime,evenin theindividualswithbetterviralloadcontrol

A 1B

Milleretal.(2001)56 _USA _Cohort_---₃_years ₆₇_patients_---₀_to_3.8

yearsold

Controlgroupwasnotincluded.Improvementinweightand weight/heightZ-scores,aswellasreductioninviralload,but therewasnoeffectonheight

B 2B

Buchaczetal.(2001)57 _USA _Prospective_---₃

years

906patients---3 monthsto18yearsold

ImprovementinweightandheightZ-scoreswithcARTcontaining proteaseinhibitor,regardlessofclinicalclassification

B 2B

USA,UnitedStatesofAmerica;DR,degreeofrecommendation;LE,levelofevidence;BMI,bodymassindex;CD4+_TL,_CD4+_T_lymphocytes;_HAART,_{highly-active}_{antiretroviral}_therapy;

(9)

Table2 Outcomerelatedtoweight/heightdevelopmentinHIV-infectedpatients(totalnumberofinfectedindividuals=51,992

childrenandadolescents),submittedtotherapywithcART.

Outcome Numberofstudies Positive---n(%)

Heightimprovement 1/44(2.27%) 244/51,992(0.47%)a

Weightimprovement 10/44(22.73%) 9789/51,992(18.83%)b

Weightandheightimprovement 33/44(75%) 41,959/51,992(80.7%)c

cART,combinedantiretroviraltherapy;HIV,humanimmunodeficiencyvirus.

a _Cames_et_al.,_2017.8

b _Jesson_et_al.,₂₀₁₇10_;_Yotebieng_et_al.,₂₀₁₅24_;_Macgratha_et_al.,₂₀₁₁30_;_Devi_et_al.,₂₀₁₁32_;_Yotebieng_et_al.,₂₀₁₀35_;_Jaspan_et_al., 200843_;_{Bandyopadhyay}_and_{Bhattacharyya,}₂₀₀₈44_;_Song_et_al.,₂₀₀₇47_;_Lodha_et_al.,₂₀₀₅50_;_Nachman_et_al.,_2002.55

c _Ramteke_et_al.,₂₀₁₇9_;_Ebissa_et_al.,₂₀₁₆17_;_Achan_et_al.,₂₀₁₆18_;_Hu_et_al.,₂₀₁₆19_;_Feucht_et_al.,₂₀₁₆20_;_Schomaker_et_al.,₂₀₁₆21_; Tekleabetal.,201622_;_{Chattopadhyay}_et_al.,₂₀₁₆23_;_Kariminia_et_al.,₂₀₁₄25_;_Shiau_et_al.,₂₀₁₃26_;_Chhagan_et_al.,₂₀₁₂27_;_Gsponer etal.,201228_;_Sutcliffe_et_al.,₂₀₁₆29_;_Diniz_et_al.,₂₀₁₁31_;_Naidoo_et_al.,₂₀₁₀33_;_Chantry_et_al.,₂₀₁₀34_;_Weigel_et_al.,₂₀₁₀36_;_Musoke etal.,201037_;_Aurpibul_et_al.,₂₀₀₉38_;_Davies_et_al.,₂₀₀₉39_;_Kabue_et_al.,₂₀₀₈40_;_Buonora_et_al.,₂₀₀₈41_;_Kekitiinwa_et_al.,₂₀₀₈42_; Zhangetal.,200745_;_Wamalwa_et_al.,₂₀₀₇46_;_Guillen_et_al.,₂₀₀₇48_;_Nachman_et_al.,₂₀₀₅49_;_Ghaffari_et_al.,₂₀₀₄51_;_Kline_et_al.,₂₀₀₄52_; Newelletal.,200353_;_Verweel_et_al.,₂₀₀₃54_;_Miller_et_al.,₂₀₀₁56_;_Buchacz_et_al.,_2001.57

Figure2 Outcome associatedwiththegrowthrelated totheuseofcARTinchildrenandadolescentsinfected byHIV. cART,

combinedantiretroviraltherapy;HIV,humanimmunodeficiencyvirus;CD4+_TL,_CD4+_T_lymphocytes.

inHIV-infectedchildren.cARTisknowntoplayaroleinthe improvementofviralandimmunologicalmarkersandmay influencethegrowthofHIV-infectedchildren.However,the increaseinanthropometricmarkers(weightandheight)did not normalizethe growth when compared to the healthy population. The earlier the diagnosis of the HIV infection and,concurrently,ofmalnutritionandtheinitiationofcART, thelowerthegrowthdeficitwhencomparedtohealthy chil-dren.PatientswithAIDSandwithoutprevioustreatmentfor antiretroviraltherapyshowbetteranthropometricresponse tocARTthanpreviouslytreatedpatients.However, unfavor-able socioeconomic and intrafamilial conditions influence treatment adherence, representing a limiting factor for

moresignificantandlong-lastingresultsoftheuseofcART inHIVinfectiontreatment.Finally,mainlyincountrieswith low economic resources to quantify the viral load, the improvementofanthropometricdataduringtheuseofcART asaparameteroftherapeuticefficacyismoreevident.

Funding

(10)

16 GolucciAPetal.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

References

1.LimaVD,LourencoL,YipB,HoggRS,PhillipsP,MontanerJS. TrendsinAIDSincidenceand AIDS-relatedmortalityinBritish Columbiabetween1981and2013.LancetHIV.2015;2:e92---7. 2.JessonJ,LeroyV.Challengesofmalnutritioncareamong

HIV-infectedchildrenonantiretroviraltreatmentinAfrica.MédMal Infect.2015;45:149---56.

3.GiménezRS,MorilloVJ.SocialepidemiologyinHIV/AIDS:what elseshouldweconsidertopreventtheHIV/AIDSprogression? SocWorkPublicHealth.2017;14:1---11.

4.Boletim Epidemiológico HIV/Aids, do Departamento de

Vig-ilância, Prevenc¸ão e Controle das Infecc¸ões Sexualmente

Transmissíveis,doHIV/AidsedasHepatitesVirais(DIAHV),da

SecretariadeVigilânciaemSaúde(SVS),doMinistériodaSaúde

(MS).2016;AnoV,Número1.

5.Benjamin DK Jr, Miller WC, Benjamin DK, Ryder RW,Weber DJ,WalterE,etal.Acomparisonofheightandweight veloc-ityasapartofthecompositeendpointinpediatricHIV.AIDS. 2003;17:2331---6.

6.Leonard EG, McComsey GA. Metabolic complications of antiretroviral therapy in children. Pediatr Infect Dis J. 2003;22:77---84.

7.SilvaRA,DuarteFH,NelsonAR,HolandaJR.AIDSepidemicin Brazil:analysisofcurrentprofile.JNursUFPE.2013;7:6039---46. 8.Jesson J, Coulibaly A, Sylla M, N’Diaye C, Dicko F, Masson D, et al. Evaluation of a nutritional support intervention in malnourishedHIV-infectedchildreninBamako,Mali.JAcquir ImmuneDeficSyndr.2017;76:149---57.

9.CamesC,PascalL,DiackA,MbodjH,OuattaraB,DiagneNR, etal.RiskfactorsforgrowthretardationinHIV-infected Sene-galesechildrenonantiretroviraltreatment.PediatrInfectDis J.2017;36:87---92.

10.RamtekeSM,ShiauS,FocaM,StrehlauR,PinillosF,PatelF,etal. Patterns ofgrowth,bodycomposition, andlipidprofilesina SouthAfricancohortofhumanimmunodeficiencyvirus-infected and uninfectedchildren: a cross-sectional study. J Pediatric InfectDisSoc.2018;7:143---50.

11.PodaGG,HsuCY,ChaoJC.MalnutritionisassociatedwithHIV infectioninchildrenlessthan5yearsinBobo-DioulassoCity, BurkinaFaso.Medicine.2017;96:e7019.

12.BeraldoRA,SantosAP,GuimarãesMP,VassimonHS,PaulaFJ, MachadoDR,etal.Bodyfatredistributionandchangesinlipid andglucosemetabolisminpeoplelivingwithHIV/AIDS.RevBras Epidemiol.2017;20:526---36.

13.Leonard EG, McComsey GA. Antiretroviral therapy in HIV-infected children: the metabolic cost of improved survival. InfectDisClinNorthAm.2005;19:713---29.

14.Eisenhut M. Anupdate on HIV in children. J Paediatr Child Health.2012;23:109---14.

15.TienPC, ChoiAI,ZolopaAR, BensonC,Tracy R,Scherzer R, etal.InflammationandmortalityinHIV-infectedadults: anal-ysisoftheFRAMStudyCohort.JAcquirImmuneDeficSyndr. 2010;55:316---22.

16.Rosenvinge MM, Doerholt K. HIV in mothers and children. Medicine(Baltimore).2013;41:461---5.

17.Ebissa G, Deyessa N, Biadgilign S. Impact of highly active antiretroviraltherapyonnutritionalandimmunologicstatusin HIV-infected childreninthelow-income countryofEthiopia. Nutrition.2016;32:667---73.

18.AchanJ,KakuruA,IkileziG,MwangwaF,PlentyA,Charlebois E, et al. Growth recovery among HIV-infected children

ran-domized to lopinavir/ritonavir or NNRTI-based antiretroviral therapy.PediatrInfectDisJ.2016;35:1329---32.

19.HuR,MuW,SunX,WuH,PangL,WangL,etal.Growthof HIV-infectedchildrenintheearlystageofantiretroviraltreatment: aretrospectivecohortstudyinChina.AIDSPatientCareSTDS. 2016;30:365---70.

20.FeuchtU,BruwaeneLV,BeckerPJ,KrugerM.Growthin HIV-infectedchildrenonlong-termantirretroviraltherapy.TropMed IntHealth.2016;21:619---29.

21.Schomaker M, Davies MA, Malateste K, Renner L, Sawry S, N’Gbeche S, et al. Growth and mortality outcomes for dif-ferent antiretroviral therapy initiation criteria in children aged 1---5 years: a causal modelling analysis. Epidemiology. 2016;27:237---46.

22.TekleabAM,TadesseBT,GirefAZ,ShimelisD,GebreM. Anthro-pometricimprovementamongHIVinfectedpre-schoolchildren followinginitiationoffirstlineanti-retroviraltherapy: implica-tionsforfollowup.PLOSONE.2016;11:1---14.

23.ChattopadhyayA,BhattacharyyaS,DharS.Agrowthand nutri-tional study of HIV seropositive children from West Bengal under direct care of medical caregivers. J Clin Diagn Res. 2016;10:14---6.

24.YotebiengM,MeyersT,BehetsF,DaviesMA,KeiserO,Ngonyani KZ,etal.Age-specific andsex-specificweight gainnorms to monitorantiretroviraltherapy inchildreninlow-incomeand middle-incomecountries.AIDS.2015;29:101---9.

25.Kariminia A, Durier N, Jourdain G, Saghayam S, Do CV, NguyenLV,etal. Weightaspredictorsofclinicalprogression andtreatmentfailure:resultsfrom theTREATAsiaPediatric HIV Observational Database. J Acquir Immune Defic Syndr. 2014;67:71---6.

26.ShiauS,ArpadiS,StrehlauR,MartensL,PatelF,CoovadiaA, etal.Initiationofantiretroviraltherapybefore6monthsofage isassociatedwithfastergrowthrecoveryinSouthAfrican chil-drenperinatallyinfectedwithhumanimmunodeficiencyvirus. JPediatr.2013;162:1138---45.

27.ChhaganMK,KauchaliS,VandenBroeck J.Clinicaland con-textualdeterminantsofanthropometricfailureatbaselineand longitudinalimprovementsafterstartingantiretroviral treat-ment among South African children. Trop Med Int Health. 2012;17:1092---9.

28.GsponerT, WeigelR,DaviesMA,BoltonC,MoultrieH,VazP, etal. Variability ofgrowthin childrenstartingantiretroviral treatmentinsouthernAfrica.Pediatrics.2012;130:e966---77. 29.Sutcliffe CG, van Dijk JH, Munsanje B, Hamangaba F,

Siny-wimaanzi P, Thuma PE, et al. Weight and height Z-scores improve after initiating ART among HIV-infected children in ruralZambia:acohortstudy.BMCInfectDis.2011;11:54. 30.McGrathaCJ,ChungMH,RichardsonBA,Benki-NugentS,Warui

D,John-StewartGC. Youngerageat ART initiationis associ-ated with morerapid growth reconstitution.AIDS. 2011;25: 345---55.

31.DinizLM,MaiaMM,CamargosLS,AmaralLC,GoulartEM,Pinto JA.ImpactofARTongrowthandhospitalizationratesamong HIV-infectedchildren.JPediatr(RioJ).2011;87:131---7. 32.Devi NP, Chandrasekaran K, Bhavani PK, Thiruvalluvan C,

Swaminathan S. Persistence of stunting after highly active antiretroviraltherapyinHIV-infectedchildreninSouthIndia. IndianPediatr.2011;48:333---4.

33.NaidooR,RennertW,LungA,NaidooK,McKerrowN.The influ-enceofnutritionalstatusontheresponsetoARTinHIV-infected childreninSouthAfrica.PediatrInfectDisJ.2010;29:511---3. 34.ChantryCJ,CerviaJS,HughesMD,AlveroC,HodgeJ,BorumP,

etal.PredictorsofgrowthandbodycompositioninHIV-infected childrenbeginningorchangingantiretroviraltherapy.HIVMed. 2010;11:573---83.

(11)

treatmentresponses in HIV-infected South African children. AIDS.2010;24:139---46.

36.WeigelR,PhiriS,ChiputulaF,GumuliraJ,BrinkhofM,Gsponer T,et al.Growth responsetoantiretroviraltreatmentin HIV-infectedchildren:acohortstudyfromLilongwe,Malawi.Trop MedIntHealth.2010;15:934---44.

37.MusokePM, Mudiope P, Barlow-Mosha LN, Ajuna P, Bagenda D,Mubiru MM,etal. Growth,immuneand viralresponsesin HIVinfectedAfricanchildrenreceivinghighlyactive antiretro-viraltherapy:aprospectivecohortstudy.BMCPediatr.2010; 10:56.

38.Aurpibul L, Puthanakit T, Taecharoenkul S, Sirisanthana T, SirisanthanaV.ReversalofgrowthfailureinHIV-infectedThai children treated with non-nucleoside reverse transcriptase inhibitor-basedantiretroviraltherapy.AIDSPatientCareSTDS. 2009;23:1067---71.

39.DaviesM-A,KeiserO,TechnauK,EleyB,RabieH,vanCutsem G,etal.,OutcomesoftheSouthAfricanNationalantiretroviral treatmentprogrammeforchildren:theIeDEASouthernAfrica collaboration.SAfrMedJ.2009;99:730---7.

40.KabueMM,KekitiinwaA,MagandaA,RisserJM,ChanW,Kline MW.Growth inHIV-infected childrenreceiving antiretroviral therapyatapediatricinfectiousdiseasesclinicinUganda.AIDS PatientCareSTDS.2008;22:245---51.

41.BuonoraS,Nogueira S, PoneMV, AloeM,OliveiraRH, Hofer C.GrowthparametersinHIV-vertically-infectedadolescentson antiretroviraltherapyinRiodeJaneiro,Brazil.AnnTrop Paedi-atr.2008;28:59---64.

42.KekitiinwaA,LeeKJ,WalkerAS,MagandaA,DoerholtK,Kitaka SB,etal.Differencesinfactorsassociatedwithinitialgrowth, CD4,and viralloadresponsestoARTinHIV-infectedchildren inKampala,Uganda,andtheUnitedKingdom/Ireland.JAcquir ImmuneDeficSyndr.2008;49:384---92.

43.Jaspan HB, Berrisford AE, Boulle AM. Two-year outcomes ofchildrenon non-nucleosidereversetranscriptase inhibitor and proteaseinhibitorregimens ina South Africanpediatric antiretroviralprogram.PediatrInfectDisJ.2008;27:993---8. 44.Bandyopadhyay A, Bhattacharyya S. Effect of pre-existing

malnutrition on growth parameters in HIV-infected chil-dren commencing antiretroviral therapy. Ann Trop Paediatr. 2008;28:279---85.

45.ZhangF,HabererJE,ZhaoY,DouZ,ZhaoH,HeY,etal. Chi-nesepediatrichighlyactiveantiretroviraltherapyobservational cohort:a1-yearanalysisofclinical,immunologic,andvirologic outcomes.JAcquirImmuneDeficSyndr.2007;46:594---8. 46.WamalwaDC,FarquharC,ObimboEM,SeligS,Mbori-NgachaDA,

RichardsonBA,etal.Earlyresponsetohighlyactive antiretrovi-raltherapyinHIV-1-infectedKenyanchildren.JAcquirImmune DeficSyndr.2007;45:311---7.

47.SongR,JelagatJ,DzomboD,MwalimuM,MandaliyaK,Shikely K,etal.EfficacyofhighlyactiveantiretroviraltherapyinHIV-1 infectedchildreninKenya.Pediatrics.2007;120:e856---61. 48.GuillenS,RamosJT,ResinoR,BellonJM,MunozMA.Impacton

weightandheightwiththeuseofARTinHIV-infectedchildren. PediatrInfectDisJ.2007;26:334---8.

49.Nachman SA, Lindsey JC, Moye J, Stanley KE, Johnson GM, KrogstadPA,etal.Growthofhumanimmunodeficiency virus-infectedchildrenreceivinghighlyactiveantiretroviraltherapy. PediatrInfectDisJ.2005;24:352---7.

50.LodhaR,UpadhyayA,KabraSK.AntiretroviraltherapyinHIV-1 infectedchildren.IndianPediatr.2005;42:789---96.

51.GhaffariG,PassalacquaDJ,CaicedoJL,GoodenowMM, Sleas-man JW. Two-year clinicaland immune outcomes in human immunodeficiencyvirus-infectedchildrenwhoreconstituteCD4 Tcells withoutcontrolofviralreplicationaftercombination antiretroviraltherapy.Pediatrics.2004;114:e604---11.

52.Kline MW, Matusa RF, Copaciu L, Calles NR, Kline NE, Schwarzwald HL. Comprehensivepediatric human immunod-eficiency virus care and treatment in Constanta, Romania: implementation of a program of highly active antiretrovi-ral therapy in a resource-poor setting. Pediatr Infect Dis J. 2004;23:695---700.

53.NewellML,BorjaMC,PeckhamC.Height,weight,andgrowthin childrenborntomotherswithHIV-1infectioninEurope. Pedi-atrics.2003;111:e52---60.

54.VerweelG,vanRossumAM,HartwigNG,WolfsTF,Scherpbier HJ,deGrootR.Treatmentwithhighlyactiveantiretroviral ther-apyinhumanimmunodeficiencyvirustype1-infectedchildren is associated with a sustained effecton growth.Pediatrics. 2002;109:E25.

55.NachmanSA,LindseyJC,PeltonS,MofensonL,McIntoshK, Wiz-niaA,etal.Growthinhumanimmunodeficiencyvirus-infected childrenreceiving ritonavir-containing antiretroviraltherapy. ArchPediatrAdolescMed.2002;156:497---503.

56.MillerTL,MawnBE,OravEJ,WilkD,WeinbergGA,Nicchitta J, etal. Theeffectof proteaseinhibitortherapy ongrowth and bodycompositioninhumanimmunodeficiencyvirustype 1-infectedchildren.Pediatrics.2001;107:e77.

57.BuchaczK,CerviaJS,LindseyJC,HughesMD,SeageGR3rd, Dankner WM, et al. Impact of protease inhibitor-containing combination antiretroviral therapies on height and weight growthinHIV-infectedchildren.Pediatrics.2001;108:e72. 58.van Rossum AM, Niesters HG, Geelen SP, Scherpbier HJ,